In vivo, aged Hri−/− mice displayed accumulation of protein aggregates and phospho-S129 α-synuclein in the central nervous system, supporting the notion that HRI-dependent cUPR may represent a novel mechanism that could be targeted to enhance clearance of protein aggregates in the context of neurodegenerative diseases. The gene discussed is EIF2AK1; the disease is neurodegenerative disease.